CN114903892A - Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer - Google Patents
Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer Download PDFInfo
- Publication number
- CN114903892A CN114903892A CN202110175637.4A CN202110175637A CN114903892A CN 114903892 A CN114903892 A CN 114903892A CN 202110175637 A CN202110175637 A CN 202110175637A CN 114903892 A CN114903892 A CN 114903892A
- Authority
- CN
- China
- Prior art keywords
- piericidin
- cervical cancer
- methoxy
- cells
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010008342 Cervix carcinoma Diseases 0.000 title claims abstract description 45
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 title claims abstract description 45
- 201000010881 cervical cancer Diseases 0.000 title claims abstract description 45
- 238000011282 treatment Methods 0.000 title claims abstract description 18
- BBLGCDSLCDDALX-LKGBESRRSA-N piericidin A Chemical compound COC=1NC(C\C=C(/C)C\C=C\C(\C)=C\[C@@H](C)[C@@H](O)C(\C)=C\C)=C(C)C(=O)C=1OC BBLGCDSLCDDALX-LKGBESRRSA-N 0.000 title abstract description 107
- 229930182661 Piericidin Natural products 0.000 title abstract description 106
- 230000015556 catabolic process Effects 0.000 claims abstract description 10
- 238000006731 degradation reaction Methods 0.000 claims abstract description 10
- 238000000338 in vitro Methods 0.000 claims abstract description 9
- 230000035755 proliferation Effects 0.000 claims abstract description 8
- 210000004027 cell Anatomy 0.000 claims description 108
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 230000006907 apoptotic process Effects 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 12
- 230000001419 dependent effect Effects 0.000 claims description 10
- 102000011727 Caspases Human genes 0.000 claims description 6
- 108010076667 Caspases Proteins 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 210000001700 mitochondrial membrane Anatomy 0.000 claims description 3
- 210000004881 tumor cell Anatomy 0.000 claims description 3
- 230000037361 pathway Effects 0.000 claims description 2
- 108091008819 oncoproteins Proteins 0.000 abstract description 15
- 102000027450 oncoproteins Human genes 0.000 abstract description 15
- 238000002474 experimental method Methods 0.000 abstract description 14
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 244000005700 microbiome Species 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000001962 electrophoresis Methods 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 8
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 8
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 8
- 229960004316 cisplatin Drugs 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 239000000975 dye Substances 0.000 description 7
- 241000701806 Human papillomavirus Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000003698 anagen phase Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012160 loading buffer Substances 0.000 description 6
- 230000004898 mitochondrial function Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 230000004913 activation Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 241000187747 Streptomyces Species 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 230000009456 molecular mechanism Effects 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 235000020183 skimmed milk Nutrition 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000036962 time dependent Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000006652 catabolic pathway Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229940127255 pan-caspase inhibitor Drugs 0.000 description 2
- TUFFYSFVSYUHPA-UHFFFAOYSA-M rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C(C=CC(N)=C2)C2=[O+]C2=C1C=CC(N)=C2 TUFFYSFVSYUHPA-UHFFFAOYSA-M 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 230000034512 ubiquitination Effects 0.000 description 2
- 238000010798 ubiquitination Methods 0.000 description 2
- 230000007730 Akt signaling Effects 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108091033409 CRISPR Proteins 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000911513 Homo sapiens Uncharacterized protein FAM215A Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000009608 Papillomavirus Infections Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 101710132594 Protein E6 Proteins 0.000 description 1
- 101710132595 Protein E7 Proteins 0.000 description 1
- 108050002653 Retinoblastoma protein Proteins 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 description 1
- 102100026728 Uncharacterized protein FAM215A Human genes 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HIMJIPRMECETLJ-UHFFFAOYSA-N Wogonin Natural products COc1cc(O)c(O)c2C(=O)C=C(Oc12)c3ccccc3 HIMJIPRMECETLJ-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009643 clonogenic assay Methods 0.000 description 1
- 231100000096 clonogenic assay Toxicity 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000007946 glucose deprivation Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- XLTFNNCXVBYBSX-UHFFFAOYSA-N wogonin Chemical compound COC1=C(O)C=C(O)C(C(C=2)=O)=C1OC=2C1=CC=CC=C1 XLTFNNCXVBYBSX-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention discloses application of a marine microorganism-derived compound 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol (Piericidin F) in treatment of E6/E7 positive cervical cancer, and experiments prove that the Piericidin F can effectively inhibit HeLa proliferation of a human cervical cancer cell in vitro and inhibit formation of HeLa cell monoclone. Experiments have found that Piericidin F can induce the degradation of oncoprotein E6/E7 by UPS and inhibit its function. Piericidin F can be obtained from marine microorganisms, is easy to separate and extract, and is an antitumor drug with a good application prospect.
Description
One, the technical field
The invention relates to application of a novel marine microorganism-derived compound 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol 6-methoxy-2- ((2E,5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethylpyridine-2, 5,7, 11-tetramethylpyridine-4-ol Piericin F) in treatment of E6/E7 positive cervical cancer, and belongs to the field of chemicals.
Second, background Art
Cervical cancer is the most common gynecological malignancy, second to breast cancer. At present, more than 46 ten thousand new cases of cervical cancer are worldwide discovered every year, while more than 13 ten thousand new cases of cervical cancer account for more than 28 percent of global cases every year in China, and clinical cases show that the cervical cancer is characterized by regional growth and advanced onset age in recent years. The cervical cancer clinical practice guideline published by the united states National Comprehensive Cancer Network (NCCN) in 2018 shows that cisplatin-based chemotherapy is a main clinical treatment method for cervical cancer. However, chronic use of cisplatin and its derivatives can lead to severe drug resistance with associated nephrotoxicity, ototoxicity and myelosuppression. There are many causes for inducing cervical cancer, and among them, persistent infection with high-risk Human Papillomavirus (HPV) is the most important cause for inducing cell canceration. Studies have shown that more than 90% of cervical cancers are associated with HPV infection. After infecting HPV virus, the virus gene is integrated into host cell genome to express pathogenic cancer protein E6/E7, which is the main pathogenic factor of cervical cancer. Because these two oncogenic proteins are selectively expressed in tumor cells, E6/E7 has been extensively studied as a potential target for E6/E7-positive cervical cancer therapy.
At present, a plurality of researches show that the natural product can target HPV E6/E7 oncoprotein at different levels and has good anti-cervical cancer activity. For example, tanshinone IIA and wogonin derived from Chinese herbal medicines can induce apoptosis of cervical cancer cells by down-regulating E6/E7 at the transcriptional level. Therefore, the search of a candidate targeting the oncoprotein E6/E7 in natural products as a potential cervical cancer resistant lead compound is a promising strategy.
Piericidins are a class of alpha-pyridone compounds produced by Streptomyces, and since the discovery in 1965, 5 classes including over 20 Piericidin classes of compounds have been isolated. Recent studies indicate that the Piericidin compounds have good antitumor activity in addition to antibacterial, anti-insect and vasodilatation activities. Therefore, we isolated and characterized a novel Piericidin alkaloid, Piericidin F, from a non-productive mutant of Streptomyces CHQ-64, investigated the cytotoxicity of Piericidin F on human cervical cancer HeLa cells, and attempted to elucidate the molecular mechanism of its activity.
The invention has not previously applied Piericidin F to the treatment of E6/E7 positive cervical cancer. And Piericidin F can be separated and extracted from streptomyces, is easy to obtain, can inhibit the proliferation of Hela cells, and is a promising antitumor drug.
The chemical name of 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol is 36-methoxy-2- ((2E,5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethylthideca-2, 5,7, 11-tetra-1-yl) -3-methylpyridin-4-ol (Piericidin F) has a chemical structure shown in figure 1.
Third, the invention
One of the objects of the present invention is to demonstrate the effect of Piericidin F against E6/E7 positive cervical cancer.
The second purpose of the invention is to detect the influence of Piericidin F on HeLa cell inhibition and clone formation in vitro.
The invention also aims to detect the influence of Piericidin F on HeLa cell apoptosis and mitochondrial membrane potential.
The fourth purpose of the invention is to explore the influence of Piericidin F on the expression and function of E6/E7 protein.
The fifth purpose of the invention is to explore the degradation pathway of Piericidin F for inducing E6/E7 protein degradation.
In order to realize the purpose, the invention adopts the technical scheme that:
the MTT technology is adopted to detect the inhibition effect of Piericidin F on the proliferation of human cervical cancer cells (HeLa) positive to E6/E7.
The plate cloning technology is adopted to detect the influence of Piericidin F on the formation of HeLa cell monoclone in vitro.
The influence of Piericidin F on HeLa cell apoptosis is detected by using Hoechst 33342 staining, WesternBlotting and MTT technology.
The influence of Piericidin F on the Mitochondrial Membrane Potential (MMP) of HeLa cells is detected by adopting a flow cytometry and SRB method.
And detecting the influence of Piericidin F on the oncoprotein E6/E7 and the function thereof by using a Western Blotting technology.
A Western Blotting technology is adopted to explore the degradation pathway of the oncoprotein E6/E7.
Compared with the prior art, the invention has the advantages and the technical effects that: the invention proves the effect of Piericidin F on resisting E6/E7 positive cervical cancer, and finds that the Piericidin F has obvious inhibition effect on HeLa cells, compared with the traditional chemotherapeutic drugs and targeted drugs, the compound can play a role from a pathogenic source E6/E7, but not a non-specific cytotoxic effect or a downstream signal path of E6/E7. Meanwhile, the molecular mechanism of treating E6/E7 positive cervical carcinoma is systematically elucidated.
Piericidin F is effective in inhibiting proliferation of human cervical cancer cells (HeLa) in vitro. Meanwhile, Piericidin F can also inhibit the formation of HeLa cell monoclonals in vitro, and can induce the HeLa cells to undergo caspase-dependent apoptosis and destroy the mitochondrial function of the HeLa cells. We further explored the molecular mechanism of Piericidin F for inhibiting HeLa cell proliferation, and found that Piericidin F can degrade oncoprotein E6/E7 and inhibit its function. Furthermore, Piericidin F induced degradation of oncoprotein E6/E7 by UPS. The results show that Piericidin F has good anti-tumor effect on E6/E7 positive cervical cancer cells and has wide application prospect.
Description of the drawings
FIG. 1 shows the chemical structure of Piericidin F in the present invention.
FIG. 2 shows that Piericidin F can inhibit proliferation of HeLa of E6/E7 positive cervical cancer cell in vitro.
FIG. 3 shows that Piericidin F in the present invention can induce caspase-dependent apoptosis in HeLa cells.
FIG. 4 shows that Piericidin F is able to disrupt mitochondrial function in HeLa cells in accordance with the present invention.
FIG. 5 shows that Piericidin F of the invention is able to degrade oncoprotein E6/E7 and inhibit its function.
FIG. 6 shows that Piericidin F in the present invention is able to induce the degradation of E6/E7 by UPS.
Fifth, detailed description of the invention
The technical scheme of the invention is further explained in detail by combining the attached drawings and test examples.
Test example 1
The influence of Piericidin F on the inhibition of the proliferation of human papilloma virus positive cervical cancer cell HeLa in vitro is explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; giemsa dye liquor; MTT; doxorubicin; DMSO.
The instrument comprises the following steps: CO 2 2 An incubator; inverting the microscope; an enzyme-labeling instrument; an ultra-clean workbench.
Experimental method MTT method: HeLa cells in a logarithmic growth phase are inoculated into a 96-well plate, Piericidin F with different concentrations is added into an experimental group after the cells are attached to the wall, DMSO diluted in equal proportion is added into a control group, adriamycin is set as a positive control (the concentration is 1 mu M), and meanwhile, a culture medium control is added. Standing at 37 deg.C for CO 2 Culturing in 5% incubator for 72 h. After the incubation, 20. mu.L of MTT solution was added to each well and the incubation was continued in the incubator for 4 h. After the incubation, the supernatant was discarded, 150. mu.L of DMSO was added to each well, and the wells were incubated in an oven at 37 ℃ for 10min, and then the absorbance (OD) was measured at a wavelength of 570nm using a microplate reader. At the same time, the cell death rate and IC were calculated using SPSS statistical software 50 。
Experimental methods plate cloning method: taking HeLa cells in logarithmic growth phase, planting 800 cells in each well into a 6-well plate, and placing the cells in an incubator for 24 h. After the cells were adherent, the cells were treated with varying concentrations of Piericidin F and incubated for 8 days. After the drug effect is finished, the upper layer culture medium is discarded, and PBS is added to clean the cells. Then adding methanol for fixation for 3min, discarding the methanol, and adding Giemsa dye solution for dyeing for 15 min. Finally, the staining results were photographed and the clones were counted.
From the experimental results of FIG. 2, it was found that P was present after 24, 48 and 72 hours of treatmentIC of iericidin F on HeLa cells 50 386.71, 75.18 and 28.80nM, respectively, indicating that Piericidin F inhibits HeLa cell proliferation in a concentration and time dependent manner. In addition, the cytotoxicity of Piericidin F on HeLa cells was also confirmed by clonogenic assays. The results show that clone formation of HeLa cells was significantly reduced after Piericidin F treatment and the clone number decreased in a concentration-dependent manner. The results show that the Piericidin F can inhibit the in-vitro proliferation of HeLa cells of human cervical cancer.
Test example 2
The influence of Piericidin F on HeLa cell apoptosis was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; hoechst 33342; Z-VAD-fmk; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper layer concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; an APS; NC film; pre-staining a Marker with protein; ECL luminescence kits; DMSO.
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; FluorChem E multifunctional imaging analysis system.
Experimental method Hoechst 33342 staining experiment: taking HeLa cells in logarithmic phase, inoculating 20 ten thousand per hole into a 6-hole plate, and placing the culture plate in a cell culture box to wait for the cells to adhere to the wall. Adding DMSO diluted by equal times into a solvent control group, adding Piericidin F with different concentrations into an experimental group, and placing the experimental group in an incubator for further culture for 36 h. After the drug effect is over, the upper layer culture medium is discarded, precooled PBS is added to wash the cells, 500 mu L of Hoechst 33342 dye with the final concentration of 5 mu g/mL is added to each hole, and incubation is carried out for 30min at 37 ℃. After the staining was finished, the staining was observed by using a fluorescent inverted microscope and photographed at 400X.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with different concentrations of Piericidin F for 24 h. The cells were then harvested and centrifuged at 1000rpm for 5min at 4 ℃. Washing with PBSThereafter, the cells were lysed with 1 × Loading Buffer at 4 ℃ for 45 min. After completion of lysis, boiling for 15min and storing at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to NC membranes. After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibody at room temperature for 1h and detected by chemiluminescence on a developer.
According to the experimental result shown in FIG. 3, the HeLa cells after 36h of Piericidin F action show brighter blue fluorescence compared with the control group, which indicates that Piericidin F can induce HeLa cells to undergo apoptosis. Furthermore, C-PARP, C-Cas3 and C-Cas9 increased, while Cas3 and Cas9 decreased after treatment with Piericidin F compared to the control group. Furthermore Bax is up-regulated, while Bcl-2 is down-regulated. In addition, the DNA damage marker γ -H2AX was increased, while the apoptosis-inhibiting protein Survivin was decreased. Moreover, the changes of the apoptosis-related proteins are concentration-dependent. These results further indicate the occurrence of apoptosis. To investigate whether Piericidin F-induced apoptosis was dependent on caspase activation, HeLa cells were pre-treated with the pan-caspase inhibitor Z-VAD-fmk and then incubated with varying concentrations of Piericidin F. The results show that HeLa cells pre-incubated with the pan-caspase inhibitor are less sensitive to Piericidin F than HeLa cells incubated with Piericidin F alone, indicating that Piericidin F-induced apoptosis is dependent on caspase activation. The results show that Piericidin F induces caspase-dependent apoptosis in HeLa.
Test example 3
The effect of Piericidin F on mitochondrial function of HeLa cells was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; DMSO; PBS; rhodamine 123; SRB dyes.
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a microplate reader.
Experimental methods flow cytometry: taking HeLa cells in logarithmic phase, inoculating 20 ten thousand per hole into a 6-hole plate, and placing the culture plate in a cell culture box to wait for the cells to adhere to the wall. Adding DMSO diluted by equal times into solvent control wells, respectively adding Piericidin F with different concentrations into experimental groups, and culturing for 36 h. After the drug action is finished, removing the upper layer culture medium, adding pancreatin digestive cells, collecting cell samples in a flow tube, centrifuging at 4 ℃, 1200rpm for 5min, removing supernatant, adding precooled PBS for resuspension, and repeatedly centrifuging according to the method. 900 μ L of PBS was added to resuspend the cells, and 100 μ L of rhodamine 123 stain (final concentration 3 μ g/mL) was added in the dark and the mixture was stained at 37 ℃ for 20 min. After dyeing is finished, centrifuging at 4 ℃ and 1200rpm for 5min, then removing supernatant, adding precooled PBS for resuspension, repeating the centrifugation step twice, adding 500 mu L PBS for resuspension, and detecting on a machine. The results of the experiment were analyzed with Summit software.
Experimental methods SRB method: taking HeLa cells in logarithmic phase, inoculating 4000/hole to a 96-hole plate, and placing the 96-hole plate in a cell culture box at 37 ℃ for culturing for 24h until the cells adhere to the wall. The next day, after the cells adhered, the upper medium was discarded, and the cells were washed with PBS. After 90 mul of sugar-free or sugar-containing culture medium is added into each hole, Piericidin F with different concentrations is added into each hole of an experimental group, DMSO diluted by equal times is added into a solvent control group, pure water with the same volume is added into a negative control group, and adriamycin is added into a positive control group. Each group is provided with 5 multiple holes and is placed in an incubator for 72 hours. After the drug effect is finished, the upper layer culture medium is discarded, 100 mu L of 10% TCA fixed cells are added into each hole, and the fixed cells are placed in a refrigerator at 4 ℃ for fixing for more than 1 h. The TCA in the 96-well plate was discarded, and the 96-well plate was rinsed 5-6 times with tap water and dried in an oven at 37 ℃. Adding 100 μ L SRB dye into each well, placing 96-well plate in 37 deg.C incubator, dyeing for 15min, washing 96-well plate with 1% glacial acetic acid for 5-6 times, and oven drying at 37 deg.C. After the 96-well plate is dried, 150. mu.L of 10mM Tris-HCl solution is added into each well, and the mixture is placed in an oven at 37 ℃ for incubation until crystals are dissolved. The absorbance (OD) at 515nm was measured with a microplate reader. According to the formula: inhibition ratio [% ] (solvent control group OD-experimental group OD)/solvent control group OD × 100% ] the inhibition ratio of the compound Piericidin F was calculated. And using IC according to the inhibition ratio of different concentrations 50 The calculator calculates the condition that Piericidin F is not sugar or contains sugarIC 72h after exposure to HeLa cells 50 The value is obtained.
From the experimental results shown in FIG. 4, we found that we used Rho-123 probe after treatment. Compared to the control group (10.54%), MMP after Piericidin F acted on HeLa cells decreased significantly, and the percentage of cells with depolarizing MMPs increased to 54.54% and 83.31% after 0.2 and 0.4 μ M PdF action, respectively, indicating that Piericidin F was able to concentration-dependently destroy MMP of HeLa cells. To further confirm whether Piericidin F affects mitochondrial function, we compared Piericidin F cytotoxicity against HeLa cells under normal (G + S +) conditions and glucose deprivation (G-S +) conditions, since tumor cells are more sensitive to chemical agents under conditions of disrupted mitochondrial function. The results showed that HeLa cells cultured under glucose-deficient conditions had higher sensitivity to the action of Piericidin F compared to HeLa cells cultured under normal conditions, confirming that Piericidin F was able to disrupt the mitochondrial function of HeLa cells.
Test example 4
The effect of Piericidin F on oncoproteins E6/E7 and their function was explored.
Cell: human cervical cancer cells (HeLa), human cervical cancer cells (CaSki), human myeloblastosis cells (HL-60), human cervical squamous carcinoma cells (SiHa), and human chronic myeloblastic leukemia cells (K562) purchased from Shanghai cell Bank of China academy of sciences.
Reagent: piericidin F; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; APS; NC film; pre-staining a Marker with protein; ECL luminescence kits; DMSO; and (4) SRB dye liquor.
Instrument CO 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; a fluorochem E multifunctional imaging analysis system; a microplate reader.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with varying concentrations of Piericidin F for 24 h. The cells were then harvested and incubated at 4 ℃ at 10 deg.CCentrifuge at 00rpm for 5 min. After washing with PBS, cells were lysed with 1 × Loading Buffer for 45min at 4 ℃. After lysis was complete, boiled for 15min and stored at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to nitrocellulose membranes (NC membranes). After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibody at room temperature for 1h and detected by chemiluminescence on a developer.
Experimental methods SRB method: and (3) taking HeLa cells in the logarithmic growth phase, planting 4000/hole into a 96-well plate, wherein each hole is 80 mu L, and placing the 96-well plate into a cell culture box for culturing for 24h until the cells adhere to the wall. The next day, the medicine is added for action. The experimental groups were treated with cisplatin (0.625-20 μ M) in the presence of 0.05 μ M Piericidin F in HeLa cells, with separate Piericidin F and cisplatin control wells and solvent control wells, doxorubicin as the positive control, and media control wells, 5 duplicate wells per group, placed in a 37 ℃ incubator for 72 h. After the drug effect was completed, the upper medium was discarded, 100. mu.L of 10% TCA was added to each well, and then the 96-well plate was fixed in a 4 ℃ freezer for 1 hour or more. Discard TCA in the plate, wash 96-well plate with tap water for 5-6 times, and dry in 37 deg.C oven. Add 100. mu.L of SRB dye to each well, stain at 37 ℃ for 15min, wash the 96-well plate 5-6 times with 1% glacial acetic acid solution, and oven dry at 37 ℃. After the 96-well plate was dried, 150. mu.L of 10mM Tris-HCl solution was added to each well, and incubated at 37 ℃ until the crystals were dissolved. The absorbance (OD) at 515nm was measured with a microplate reader. According to the formula: inhibition ratio [% ] (solvent control group OD-experimental group OD)/solvent control group OD × 100% ] the inhibition ratio of the compound Piericidin F was calculated. Calcusyn was used to calculate Combination Index (CI) with CI values >1, 1 and <1 indicating antagonism, additive effect and synergy respectively.
According to the experimental results of FIG. 5, Piericidin F was found to significantly reduce the level of E6/E7 in cells in a concentration-dependent manner and a time-dependent manner. Furthermore, the down-regulation of E6/E7 by Piericidin F was accompanied by an increase in C-PARP, indicating that a decrease in E6/E7 is responsible for Piericidin F-induced HeLa apoptosis. p53 and Rb are the main targets of E6/E7 and are rapidly degraded by E6/E7. Due to the fact thatWe hypothesized that Piericidin F-induced down-regulation of E6/E7 might lead to up-regulation of p53 and Rb. P53 and Rb proteins increased in a concentration-dependent manner following Piericidin F treatment. Furthermore, we also tested E6/E7 changes in other HPV-positive cervical cancer cell lines after Piericidin F action, such as CaSki and SiHa. As shown, Piericidin F significantly reduced the levels of E6/E7 in CaSki and SiHa cells, while the levels of C-PARP increased significantly with the decrease in E6/E7, and Piericidin F also showed a significant effect on CaSki (IC) 50 3.70 μ M) and SiHa (IC) 50 5.35 μ M) was observed.
E6/E7 has been reported to activate the PI3K/AKT signaling pathway and the STAT 3-mediated signaling pathway, which are required for cervical cells to become cancerous. After oncoprotein E6/E7 was reduced by Piericidin F, the phosphorylation levels of AKT and STAT3 were significantly reduced, while the background protein levels of AKT and STAT3 were unaffected. These results indicate that oncoprotein E6/E7 is degraded by Piericidin F and loses the function of signaling downstream. To determine whether the reduction in STAT3 and AKT phosphorylation in HeLa cells was caused by a reduction in E6/E7, we examined the levels of p-STAT3 and p-AKT in E6/E7 negative HL-60 and K562 cell lines. As shown, the background proteins of STAT3 and AKT and their levels of phosphorylation did not change significantly after treatment with Piericidin F, indicating that Piericidin F did not directly affect the levels of phosphorylation of STAT3 and AKT, but rather affected the activation of STAT3 and AKT by downregulating E6/E7 levels. Activation of AKT and STAT3 was reported to contribute to resistance of HeLa cells to cisplatin. Therefore, inhibition of AKT and STAT3 activation may make HeLa cells more sensitive to cisplatin. Therefore, we examined the combined effect of Piericidin F and cisplatin on HeLa cells. The results show that the CI index is much less than 1, indicating that the combined administration of Piericidin F and cisplatin shows a significant synergistic effect in inhibiting HeLa cell proliferation. These results demonstrate that Piericidin F can reduce oncoprotein E6/E7 levels and subsequently inhibit their signaling function.
Test example 5
The pathway of Piericidin F to degrade oncoproteins E6/E7 was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper layer concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; NC film; pre-staining a Marker with protein; ECL luminescence kit
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; FluorChem E multifunctional imaging analysis system.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with different concentrations of Piericidin F for 24 h. The cells were then harvested and centrifuged at 1000rpm for 5min at 4 ℃. After washing with PBS, the cells were lysed with 1 × Loading Buffer for 45min at 4 ℃. After lysis was complete, boiled for 15min and stored at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to NC membranes. After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibodies for 1h at room temperature and detected by chemiluminescence by a developer.
According to the experimental results of FIG. 6, it was found that in the presence of CHX (a translation inhibitor), E6/E7 decreased more rapidly after Piericidin F action, compared to the control group, indicating that Piericidin F accelerated the degradation of E6/E7 at the protein level. In cervical cancer cells, levels of E6/E7 are regulated by UPS. To determine whether proteasomes were involved in Piericidin F-induced degradation of E6/E7, we used the proteasome inhibitor MG132 to detect levels of E6/E7 after Piericidin F treatment. The results show that Piericidin F alone induced down-regulation of E6/E7, while MG132 reversed this reduction, indicating that proteasomes mediated Piericidin F-induced degradation of E6/E7. Furthermore, in the presence of Piericidin F, the levels of C-PARP were reduced by MG132, further demonstrating that degradation of E6/E7 triggers Piericidin F-induced apoptosis. These results indicate that UPS is activated by Piericidin F to increase the degradation of oncoprotein E6/E7 and also mediates apoptosis of HeLa cells.
Proteins are usually ubiquitinated before being degraded by the proteasome. We examined the ubiquitination level of E6 protein after Piericidin F action by IP experiments. The results show that Piericidin F increased the ubiquitination level of E6 protein and appeared time-dependent compared to the blank group, further indicating that UPS is involved in Piericidin F-induced E6/E7 degradation.
Claims (7)
- The use of 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol and its derivatives for the treatment of E6/E7 positive cervical cancer, having the chemical formula:
- 2. the anti-cervical cancer effect of claim 1, wherein said tumor cells are: a human cervical cancer cell line positive for E6/E7.
- 3. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can be used for preparing a medicine for treating E6/E7 positive cervical cancer.
- 4. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can effectively inhibit the proliferation of HeLa cells in vitro.
- 5. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can induce caspase-dependent apoptosis in HeLa cells.
- 6. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can destroy the mitochondrial membrane potential of HeLa cells.
- 7. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can induce the degradation of E6/E7 protein through UPS pathway and inhibit the function of the protein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110175637.4A CN114903892A (en) | 2021-02-09 | 2021-02-09 | Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110175637.4A CN114903892A (en) | 2021-02-09 | 2021-02-09 | Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114903892A true CN114903892A (en) | 2022-08-16 |
Family
ID=82760993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110175637.4A Pending CN114903892A (en) | 2021-02-09 | 2021-02-09 | Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114903892A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008174508A (en) * | 2007-01-19 | 2008-07-31 | National Institute Of Advanced Industrial & Technology | New piericidine derivative or its salt, method for producing the same and antitumor agent containing the derivative as active ingredient |
| CN109414419A (en) * | 2016-06-15 | 2019-03-01 | 德国癌症研究中心 | Treatment of cancer is carried out by targeted energy metabolism simultaneously and internal pH |
| WO2020234454A1 (en) * | 2019-05-23 | 2020-11-26 | Deutsches Krebsforschungszentrum | Combination treatment of cancer targeting energy metabolism and intracellular ph |
| US20220079912A1 (en) * | 2018-09-14 | 2022-03-17 | University Of Mississippi | Anticancer formulation |
-
2021
- 2021-02-09 CN CN202110175637.4A patent/CN114903892A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008174508A (en) * | 2007-01-19 | 2008-07-31 | National Institute Of Advanced Industrial & Technology | New piericidine derivative or its salt, method for producing the same and antitumor agent containing the derivative as active ingredient |
| CN109414419A (en) * | 2016-06-15 | 2019-03-01 | 德国癌症研究中心 | Treatment of cancer is carried out by targeted energy metabolism simultaneously and internal pH |
| US20220079912A1 (en) * | 2018-09-14 | 2022-03-17 | University Of Mississippi | Anticancer formulation |
| WO2020234454A1 (en) * | 2019-05-23 | 2020-11-26 | Deutsches Krebsforschungszentrum | Combination treatment of cancer targeting energy metabolism and intracellular ph |
Non-Patent Citations (2)
| Title |
|---|
| XIAONING HAN，等: "Geranylpyrrol A and Piericidin F from Streptomyces sp. CHQ-64 ΔrdmF", 《J. NAT. PROD.》 * |
| 丁衍，等: "海洋放线菌抗肿瘤活性物质的研究进展", 天然产物研究与开发 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cheng et al. | Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells | |
| Lv et al. | ROS-dependent Atg4 upregulation mediated autophagy plays an important role in Cd-induced proliferation and invasion in A549 cells | |
| Chen et al. | Astragalin-induced cell death is caspase-dependent and enhances the susceptibility of lung cancer cells to tumor necrosis factor by inhibiting the NF-κB pathway | |
| Min et al. | Astragaloside IV inhibits the progression of liver cancer by modulating macrophage polarization through the TLR4/NF-κB/STAT3 signaling pathway | |
| Feng et al. | Basil polysaccharide inhibits hypoxia-induced hepatocellular carcinoma metastasis and progression through suppression of HIF-1α-mediated epithelial-mesenchymal transition | |
| Li et al. | Inhibitory effect of berberine on human skin squamous cell carcinoma A431 cells | |
| Payon et al. | Mechanism of cepharanthine cytotoxicity in human ovarian cancer cells | |
| Cheng et al. | CRA (Crosolic Acid) isolated from Actinidia valvata Dunn. Radix induces apoptosis of human gastric cancer cell line BGC823 in vitro via down-regulation of the NF-κB pathway | |
| Wang et al. | Wogonoside induces cell cycle arrest and mitochondrial mediated apoptosis by modulation of Bcl-2 and Bax in osteosarcoma cancer cells | |
| Qian et al. | Ginsenoside-Rh2 inhibits proliferation and induces apoptosis of human gastric cancer SGC-7901 side population cells | |
| Zhu et al. | ATG7 deficiency promote apoptotic death induced by Cisplatin in human esophageal squamous cell carcinoma cells | |
| Jakimov et al. | Androstane derivatives induce apoptotic death in MDA-MB-231 breast cancer cells | |
| Xiao et al. | Polygalacin D suppresses esophageal squamous cell carcinoma growth and metastasis through regulating miR-142-5p/Nrf2 axis | |
| Ma et al. | Tumor suppressive role of rottlerin in cancer therapy | |
| Zhou et al. | Piperlongumine induces apoptosis and G2/M phase arrest in human osteosarcoma cells by regulating ROS/PI3K/Akt pathway | |
| Al-Harbi et al. | Apoptosis induction, cell cycle arrest and in vitro anticancer potentiality of Convolvulus spicatus and Astragalus vogelii | |
| Yang et al. | Endoplasmic reticulum stress regulates proliferation, migration and invasion of human ovarian cancer SKOV3 cells through PI3K/AKT/mTOR signaling pathway | |
| Gan et al. | Natural product pectolinarigenin exhibits potent anti-metastatic activity in colorectal carcinoma cells in vitro and in vivo | |
| Xin et al. | Girinimbine inhibits the proliferation of human ovarian cancer cells in vitro via the phosphatidylinositol-3-kinase (PI3K)/akt and the mammalian target of rapamycin (mTOR) and Wnt/β-catenin signaling pathways | |
| Chen et al. | Anti-cancer drug anlotinib promotes autophagy and apoptosis in breast cancer | |
| Teng et al. | Effect of Rhizoma paridis total saponins on apoptosis of colorectal cancer cells and imbalance of the JAK/STAT3 molecular pathway induced by IL-6 suppression | |
| Sun et al. | Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer | |
| Li et al. | Anthraquinone derivative C10 inhibits proliferation and cell cycle progression in colon cancer cells via the Jak2/Stat3 signaling pathway | |
| CN114903892A (en) | Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer | |
| CN109528712B (en) | Use of 9-methyl-3, 6-diacetylcarbazole for the treatment or prevention of neoplastic diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220816 |